Stem Cell Mobilization in Diabetes

糖尿病中的干细胞动员

基本信息

批准号：
7675341
负责人：
STEPHEN RAYMOND THOM
金额：
$ 23.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7675341
关键词：
Acute Adult Animal Model Animals Biochemical Biological Assay Biopsy Blood Cells Blood Platelets Blood Vessels Bone Marrow Cell physiology Cells Characteristics Clinical Clinical Management Clinical Treatment Data Diabetes Mellitus Diabetic mouse Diabetic ulcer Elements Exploratory/Developmental Grant Flow Cytometry Foundations Funding Glucose Goals Growth Factor Guidelines Healed Heat shock proteins Hematopoietic Stem Cell Mobilization Histocytochemistry Home environment Homing Human Hyperbaric Oxygen Hyperglycemia Impaired wound healing Insulin Leg Ulcer Link Measurement Measures Mediating Methods Monitor Multi-Institutional Clinical Trial Neuropathy Nitric Oxide Patients Peptide Hydrolases Peripheral Population Procedures Protease Inhibitor Protein Kinase C Punch Biopsy Randomized Clinical Trials Refractory Regulation Reporting Research Research Project Grants Role Severities Stem cells Surrogate Markers Techniques Testing Translational Research Treatment Efficacy Ulcer Vascularization Wound Healing base caveolin 1 cell growth clinical practice diabetes management diabetic diabetic patient diabetic wound healing enzyme activity glycemic control healing human NOS3 protein improved multidisciplinary neovascularization non-diabetic novel patient population public health relevance response stem tool wound

项目摘要

DESCRIPTION (provided by applicant): This proposal outlines a translational research plan to investigate the role of stem/progenitor cell (SPCs) mobilization and recruitment for healing diabetic neuropathic lower extremity ulcers. Techniques will involve blood cell flow cytometry, histochemistry on wound biopsies, and a novel method for measuring endothelial nitric oxide synthase (eNOS) activity in intact platelets. As a tool to hasten SPCs mobilization from the bone marrow we will use hyperbaric oxygen (HBO2), which stimulates bone marrow eNOS activity. We hypothesize that eNOS activity is impaired in diabetics and that improved glucose management will improve eNOS activity, SPCs mobilization from the bone marrow, SPCs recruitment to wounds, and these changes will stimulate wound healing. Specific aim 1. To document eNOS activity as a variable for SPCs mobilization in diabetics. Trials will be carried out with diabetics and normal, healthy adults. The primary focus is to test whether platelet eNOS activity correlates with baseline number of circulating SPCs and HBO2-mediated SPCs mobilization. A secondary goal is to examine whether eNOS activity is correlated with glycemic control. Specific aim 2. To assess feasibility of evaluating wound variables associated with neo-vascularization and whether they correlate with healing in diabetic patients. This study will involve populations of diabetics with neuropathic ulcers of varying severity who are undergoing clinical treatments according to current recommended guidelines. In a sub-set of patients with refractory wounds, this includes hyperbaric oxygen. We will examine how clinical practices influence eNOS activity, circulating SPCs, and biochemical characteristics within wounds including the presence of growth factors, proteases and inhibitors of proteases. SPCs recruitment and biochemical characteristics will be compared between the existing neuropathic ulcer and an acute punch biopsy wound. We hypothesize that better management of diabetes will improve eNOS activity, and that wound healing rate depends on the number of circulating SPCs and biochemical factors within the wound that influence SPCs homing and function. These studies will be carried out by a multidisciplinary team. Information obtained will provide a foundation for a multi-centered clinical trial to test whether diabetic management can modulate SPCs mobilization and recruitment to wounds, whether eNOS activity is correlated with these changes, and whether diabetic ulcer healing is related to these improvements. PUBLIC HEALTH RELEVANCE: This proposal outlines a research plan to investigate the role of stem/progenitor cell (SPCs) mobilization and recruitment for healing diabetic neuropathic lower extremity ulcers. We hypothesize that endothelial nitric oxide synthase (eNOS) activity is impaired due to diabetes and glucose management. As a tool to stimulate mobilization of SPCs from the bone marrow we will use hyperbaric oxygen (HBO2), and we will determine how clinical management practices - including HBO2 - modify circulating SPCs as well as wound characteristics.

描述（由申请人提供）：该提案概述了一项转化研究计划，旨在研究干/祖细胞（SPC）动员和募集在治疗糖尿病神经性下肢溃疡中的作用。技术将涉及血细胞流式细胞术、伤口活检的组织化学以及测量完整血小板中内皮一氧化氮合酶（eNOS）活性的新方法。作为加速 SPC 从骨髓动员的工具，我们将使用高压氧 (HBO2)，它会刺激骨髓 eNOS 活性。我们假设糖尿病患者的 eNOS 活性受损，改善葡萄糖管理将改善 eNOS 活性、SPC 从骨髓动员、SPC 募集到伤口，这些变化将刺激伤口愈合。具体目标 1. 记录 eNOS 活性作为糖尿病患者 SPC 动员的变量。试验将在糖尿病患者和正常健康成年人中进行。主要重点是测试血小板 eNOS 活性是否与循环 SPC 的基线数量和 HBO2 介导的 SPC 动员相关。第二个目标是检查 eNOS 活性是否与血糖控制相关。具体目标 2. 评估评估与新血管形成相关的伤口变量的可行性以及它们是否与糖尿病患者的愈合相关。这项研究将涉及患有不同严重程度的神经性溃疡的糖尿病患者群体，他们正在根据当前推荐的指南接受临床治疗。对于难治性伤口患者的子集，这包括高压氧。我们将研究临床实践如何影响 eNOS 活性、循环 SPC 和伤口内的生化特征，包括生长因子、蛋白酶和蛋白酶抑制剂的存在。将比较现有神经性溃疡和急性穿孔活检伤口之间的 SPC 募集和生化特征。我们假设更好的糖尿病管理将改善 eNOS 活性，并且伤口愈合率取决于循环 SPC 的数量以及伤口内影响 SPC 归巢和功能的生化因素。这些研究将由多学科团队进行。获得的信息将为多中心临床试验奠定基础，以测试糖尿病管理是否可以调节 SPC 动员和募集到伤口、eNOS 活性是否与这些变化相关，以及糖尿病溃疡愈合是否与这些改善相关。公共健康相关性：该提案概述了一项研究计划，旨在调查干/祖细胞 (SPC) 动员和募集在治疗糖尿病神经性下肢溃疡中的作用。我们假设内皮一氧化氮合酶 (eNOS) 活性因糖尿病和血糖管理而受损。作为刺激骨髓中 SPC 动员的工具，我们将使用高压氧 (HBO2)，并且我们将确定临床管理实践（包括 HBO2）如何改变循环 SPC 以及伤口特征。